Chemo yes or no? This decision to make due to a gene
expression test is too uncertain for breast cancer patients, writes the IQWiG -
and thus fires again the dispute.

BY ADELHEID MÜLLER-LISSNER

Difficult Decision. It is not always clear which breast
cancer patient really needs chemotherapy. Gene expression tests should help

.

"Overall, the IQWiG concludes that there is currently
no evidence for a benefit or harm to a biomarker-based strategy to decide
whether or not to undergo adjuvant chemotherapy for primary breast
cancer."

MORE AFTER BREAK

For outsiders, this rate may sound specialist-chinese. The
analysis published today by the Institute for Quality and Efficiency in Health
Care (IQWiG), commissioned by the Federal Joint Committee (G-BA), is likely to be
affected by affected women.

With the tests, whose usefulness is questioned here, they
ultimately combine the hope of saving themselves with a lengthy, strenuous and
possibly purchased with life-long health problems.

"To withhold a test
from a woman, despite all the recommendations from the scientific side and the
big breast cancer congresses in the USA and here in Germany, is similar in my
eyes to a personal injury," says one of the emotional (open) letters of
affected women In 2013 with the then Federal Minister of Health Daniel Bahr.

Who needs a chemo? Whom does she do more than she does?

Why is? Around 70,000 women are diagnosed with breast cancer
every year in Germany. The question of whether further treatment is necessary
in addition to an operation is then quickly in the room. With the greatest
anxiety, the women usually wait for a supportive chemotherapy. It is intended
to prevent the cancer from returning and spreading elsewhere in the body. Women
who have only a minimal risk of such a relapse would be unnecessarily burdened
with the toxic treatment for cells. Others are very likely to save their lives.
But who belongs to which group?

"The chemotherapy has improved the cure rate in
breast cancer - but it has been chemotherapy too much," says gynecologist
Isabell Witzel, head of the breast center at the University Hospital in Hamburg
(UKE). The guidelines list criteria for the physicians to address and discuss
them in their tumor conferences. This includes questions such as: How big is
the tumor? Are lymph nodes infected? How fast do cancer cells grow? What is the
proportion of cells that multiply? Last but not least: Do receptors for
female sex hormones, which influence the growth, and large amounts of the
growth factor HER2 in the cancer tissue are found? Usually, the answers are a
clear decision.

The tests determine which genes are active in the tumor

But there are controversial borderline cases - especially
when the tumor has receptors for estrogen and progesterone when it is
HER2-negative and no or at most three lymph nodes are infected. "The
patient's individual risk must be discussed here," says Michael Untch,
chief physician of the women's clinic and head of the Interdisciplinary Breast
Center at the Helios Clinic in Berlin-Buch. Tests that help in the decision are
basically welcome.

In the meantime, pathologists are investigating the two
proteins uPA and PAI 1 more frequently during the surgical operation, in order to
estimate the prognosis of breast cancer patients without involvement of the
lymph nodes.

And there have been several tests on the market, with which
one can find out how strong up to 70 different genes in the tumor are active.
Partially, one can use paraffin-preserved tissue for this purpose. Oncotype DX,
EndoPredict, PAM 50 and MammaPrint - these are currently the best known names.

According to IQWiG, such tests are questionable [?under consideration] for about 20,000 women every
year.

The experts of the IQWiG were waiting for a large study

They should be used "only in selected patients, if all
other criteria do not permit a therapy decision," according to a current
opinion of the Arbeitsgemeinschaft Gynäkologische Onkologie.

The 2012 breast
cancer guideline, which is currently being revised, states: "The use of
analyzes for gene expression to assess prognosis or therapy responses is not
sufficiently validated and therefore can not be recommended."

The IQWiG had retained its final assessment in order to
await the results of the so-called Mindact study on the MammaPrint test from
the Dutch company Agendia. Six other studies had previously excluded the
investigators from the analysis because of missing data or not quite
appropriate questions. The PlanB study of the West German study group (WSG) on
the Oncotype DX test produced encouraging results, but can only date with an observation
period of three years.

"You can not advise against conscience
chemotherapy"

For the Mindact study, which focuses on IQWiG, 6696 women
were diagnosed with the risk that the cancer could report again after the first
treatment, according to the conventional criteria and the gene expression test
MammaPrint. If clinical and genetic assessments were consistent with the risk,
a clear decision for or against chemotherapy could be made. If they diverged
from one another, this important point was randomly placed with the consent of
the participants. In August, the first results of the investigation were
published in the "New England Journal of Medicine".

It was important for the assessment of the IQWiG as to how
those 46 per cent of the women after five years had, which had a favorable
result in the biomarker test, but high clinically recognizable risks. 94.4
percent of the women in this group who had not received chemotherapy had not
received any long-distance resettlement of the tumor, 95.9 percent of women
with chemotherapy had spared this fate, a statistically insignificant
difference of 1.5 percent . Due to various uncertainties, however, he could
also be up to four percent, according to the IQWiG. "At the present time,
a woman with a clinically high and genetically low risk can not advise against
a good chemotherapy chemotherapy", says the press release.

In the other scale, however, the hardships and also the
possible late effects of chemotherapy occur. The side effects at the heart can
be seen years later. "The calculation of the IQWiG has been set up outside
the clinical routine and would hardly be reproduced by a patient who is
undergoing six-month chemotherapy," says Oleg Gluz, Oberarzt at the Brustzentrum
Niederrhein in Mönchengladbach and Scientific Coordinator of the WSG.

The
situation was exacerbated by the fact that the patients were generally older
than those included in studies during the care day. Up to now there have been
only vague statements on the side effects, says Daniel Fleer from the IQWiG
Department of Non-Medication, who supervised the report. The authors of the
Mindact study, gathering information about this, missed the opportunity to make
public their findings on the undesirable effects [harms] of chemotherapy.

That the tests could spare some women a too far-reaching
therapy is, however, only one side of the coin. If a test with a low clinical
risk poses a high risk in the gene signature, it can look exactly the opposite.
However, Untch criticizes the fact that chemotherapy is of use in these cases,
but it has not yet been proved, even if the advertising brochures of some
manufacturers are different. It would be very difficult to decide if a woman
with an average risk of chemotherapy should be advised. "Again, the data
is unclear," he says.

"The evaluation puts us back in the 1980s"

The IQWiG calls for long-term results. "Five years of
follow-up are much too short," says Brecht-cancer expert Untch. Especially
in patients who have breast cancer antennas for female sex hormones and is Her2
negative, metastases often occur much later - "up to 25 years after the
diagnosis". On this point the IQWiG's perspective is understandable, says
Stefan Wiemann, head of the Molecular Genome Analysis department at the German
Cancer Research Center in Heidelberg. "The five-year period of the Mindact
study is, in fact, inadequate to make a final assessment of the predictive
power of this test."

Should use of the test be delayed under these
circumstances? This is a difficult question, especially for doctors who have to
make therapy decisions daily with their patients. According to Untch, the tests
were on the market precisely because the so-called group had so much
uncertainty as to whether they still needed chemotherapy in addition to
antihormonal treatment. There is something more secure now, says his colleague
Isabell Witzel. "The Mindact study confirms that in low-risk women,
according to genetic testing but high clinical risk, chemotherapy can be
dispensed with." Oleg Gluz demands that at least the well-tested tests are
paid by the health insurance companies in these patients. "Unfortunately,
the IQWiG assessment in Germany is returning to the 1980s, 1990s, when the
knowledge of tumorbiology was still insufficient."

Politics on the back of the patients

The scenario is tricky. This is partly due to the fact that
diagnostic tests are different from those for medicinal products. The breast
cancer expert Rolf Kreienberg, president of the Arbeitsgemeinschaft der
Wissenschaftliche Medizinische Fachgesellschaften and external expert for the
IQWiG investigation, calls for such tests to clarify the evidence before the
market launch by studies "so that a clear starting position exists and not
with the Patients or their back policy. "

In this case it is too late.
Patients can only hope that in five years more clarity will prevail.

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About Me

Bruce Quinn MD PhD is an expert on health reform, innovation, and Medicare policy. He helps both large and small companies understand and overcome hurdles to commercialization, as well as craft business strategies for a changing environment. CONTACT Dr. Quinn through www.brucequinn.com. BACKGROUND: Dr. Quinn has worked in academic medicine, Accenture business strategies, and for the Medicare program. EDUCATION: Stanford MD/PhD, MIT Postdoc, Kellogg MBA.